Targeted Proteomics of Resilient Cognition in Aging Abstract Cognition in later life deteriorates when age-associated degenerative and other pathological processes overwhelm the brain's capacity to withstand, counteract or compensate for those processes through neuroplastic, reparative responses. Thus, while clinicopathological correlation studies show significant associations of plaques, tangles, infarctions and other lesions with cognitive impairment, the relationships are imperfect, and it is increasingly recognized that some elderly persons may have abundant pathology and yet still are unimpaired. We propose an innovative clinicopathological approach in the richly characterized Religious Orders Study (ROS) cohort to identify candidate proteins and pathways that best confer cognitive resilience despite the presence of neurodegenerative disease pathologies. To accomplish this we apply non-biased stratification in the ROS cohort to identify three distinct test groups of 60 each: 1) AD-Dementia (dementia with abundant plaque and tangle pathology), 2) AD-Resilient (normal cognition despite abundant AD plaque. tangle and other pathology), and 3) Healthy (normal cognition and minimal AD or other pathology). We will measure the expression of >500 proteins that span functional families of apoptosis, synaptic neurotransmission and neuroplasticity, metabolic, inflammatory, cytoskeletal, signal transduction pathways and others. We will test two hypotheses that pro-apoptotic proteins and synaptic plasticity proteins differentiate the clinicopathological category groups and we will conduct machine learning approaches to further identify these and novel analytes that best predict categories. Based on these analyses, we will generate a targeted multi-analyte immunoassay panel. This will be used to validate the association of candidate proteins with cognitive resilience in another set of 480 ROS cases. Our focus on the neurobiology of resilient brain aging will be an important counterpoint and complement to historical and current efforts focused on the neurobiology of disease pathology. PUBLIC HEALTH RELEVANCE: Targeted Proteomics of Resilient Cognition in Aging Cognitive decline in aging arises when age-associated neuropathological processes overwhelm the brain's capacity to withstand or adapt to those processes. We propose an innovative clinicopathological approach to identify candidate proteins and pathways that best confer cognitive resilience despite the presence of neurodegenerative disease pathologies. Using antibody microarrays for discovery and multi-analyte immunoassays for validation in brain tissues from participants of the Religious Orders Study, we will identify potential novel mechanisms of cognitive resilience in aging.